Field of the Invention
This invention pertains to the discovery that polypeptides that bind to CGRP or CGRP receptor and/or other polypeptides which inhibit the CGRP/CGRP receptor interaction such as anti-CGRP or anti-CGRP receptor antibodies and antibody fragments or fragments of CGRP or the CGRP receptor which inhibit the CGRP/CGRP receptor interaction may be used to treat or prevent diarrhea, especially diarrhea associated with conditions or treatments that result in increased levels of CGRP. Exemplary conditions and treatments involving increased CGRP are identified herein. The invention in particular relates to methods of inhibiting, preventing or treating diarrhea and/or maintaining electrolyte balance and fluid levels in the colon of a subject having a condition or treatment associated with elevated CGRP levels that result in diarrhea and/or increased flux of electrolytes and fluids from the colon comprising administering an effective amount of an anti-CGRP antibody or anti-CGRP antibody fragment. Exemplary conditions include by way of example functional bowel disorder and inflammatory bowel diseases, bacterial or viral infections, and more specifically gastro-esophageal reflux, dyspepsia, irritable bowel syndrome, functional abdominal pain syndrome, diverticulosis, and diverticulitis, Crohn's disease, ileitis, collagenous colitis, lymphocytic colitis, ulcerative colitis, cancers or cancer treatments associated with increased CGRP and diarrhea such as chemotherapy, radiation, medullary thyroid carcinoma, and colorectal cancer.
In addition the present invention provides methods of screening polypeptides such as anti-CGRP or anti-CGRP receptor antibodies and fragments thereof (including Fab fragments) having binding specificity to human Calcitonin Gene Related Peptide (hereinafter “CGRP”) as well as fragments of CGRP or a CGRP receptor in animal models to determine the in vivo effects thereof, especially their ability to antagonize the adverse side effects of CGRP and to treat conditions involving excess CGRP, especially CGRP associated conditions or treatments associated with diarrhea. The invention also pertains to methods of screening for diseases and disorders associated with increased CGRP, which are associated with diarrhea and specific therapeutic regimens for preventing or treating diseases and disorders that involve CGRP associated diarrhea by administering said antibodies or fragments thereof, alone or in association with other actives.
Description of Related Art
Calcitonin Gene Related Peptide (CGRP) is produced as a multifunctional neuropeptide of 37 amino acids in length. Two forms of CGRP, the CGRP-alpha and CGRP-beta forms, exist in humans and have similar activities. CGRP-alpha and CGRP-beta differ by three amino acids in humans, and are derived from different genes. The CGRP family of peptides includes amylin, adrenomedullin, and calcitonin, although each has distinct receptors and biological activities. Doods, H., Curr. Op. Invest. Drugs, 2(9):1261-68 (2001).
CGRP is released from numerous tissues such as trigeminal nerves, which when activated release neuropeptides within the meninges, mediating neurogenic inflammation that is characterized by vasodilation, vessel leakage, and mast-cell degradation. Durham, P. L., New Eng. J. Med., 350 (11):1073-75 (2004). The biological effects of CGRP are mediated via the CGRP receptor (CGRP-R), which consists of a seven-transmembrane component, in conjunction with receptor-associated membrane protein (RAMP). CGRP-R further requires the activity of the receptor component protein (RCP), which is essential for an efficient coupling to adenylate cyclase through G proteins and the production of cAMP. Doods, H., Curr. Op. Invest. Drugs, 2(9):1261-68 (2001).
Migraines are neurovascular disorder affecting approximately 10% of the adult population in the U.S., and are typically accompanied by intense headaches. Approximately 20-30% of migraine sufferers experience aura, comprising focal neurological phenomena that precede and/or accompany the event. CGRP is believe to play a prominent role in the development of migraines. For example, plasma concentrations of CGRP were identified elevated in jugular venous blood during the headache phase of migraines, to the exclusion of other neuropeptides. Moreover, according to Arulmozhi et al, the following has been identified in migraine sufferers: (1) a strong correlation between plasma CGRP concentrations and migraines; (2) the infusion of CGRP produced a migraine-like headache; (3) baseline CGRP levels were elevated; and (4) changes in plasma CGRP levels during migraine attacks significantly correlated with headache intensity. Arulmozhi, D. K., et al., Vas. Pharma., 43: 176-187 (2005). In addition, in the Journal of the International Association for the Study of Pain PII:S0304-3959(11)00313-7; doi:10.1016/j.pain.2011.04.033, published online 6 Jun. 2011, Hou et al., reported that keratinocyte expression of calcitonin gene-related peptide β has implications for neuropathic and inflammatory pain mechanisms.
One effective treatment for migraines is the administration of triptans, which are a family of tryptamine-based drugs, including sumatriptan and rizatriptan. Members of this family have an affinity for multiple serotonin receptors, including 5-HT1B, 5-HT1D, and 5-HT1F. Members of this family of drugs selectively constrict cerebral vessels, but also cause vasoconstrictive effects on coronary vessels. Durham, P. L., New Eng. J. Med., 350 (11):1073-75 (2004). There is a theoretical risk of coronary spasm in patients with established heart disease following administration, and cardiac events after taking triptans may rarely occur. Noted to be contraindicated for patients with coronary vascular disease.
Similarly, pain may often be addressed through the administration of certain narcotics or non-steroidal anti-inflammatory drugs (NSAIDs). However, the administration of these treatments may occur at the cost of certain negative consequences. NSAIDs have the potential to cause kidney failure, intestinal bleeding, and liver dysfunction. Narcotics have the potential to cause nausea, vomiting, impaired mental functioning, and addiction. Therefore, it is desirable to identify alternative treatments for pain in order to avoid certain of these negative consequences.
CGRP is believed to play a role in a multitude of diseases and disorders, including but not limited to migraines, headaches, and pain. Due to the perceived involvement of CGRP in these diseases and disorders, there remains a need in the art for compositions and methods useful for preventing or treating diseases and disorders associated with CGRP, while avoiding adverse side effects. There especially remains a need in the art for compositions or methods that reduce or inhibit diseases or disorders associated with CGRP, such as migraines, headaches, and pain.
Aside from the afore-mentioned conditions there is a need for treating other conditions or adverse side effects that are associated with increased CGRP. In this regard there has been some anecdotal evidence reported in the literature which suggest that increases in CGRP levels may have a role in some diseases associated with diarrhea. For example, it was reported by Rolston et al. in Digestive Diseases and Sciences, (April 1989) 34(4):612-6, “Intravenous calcitonin gene-related peptide stimulates net water secretion in rat colon in vivo” that exogenous calcitonin gene-related peptide has an effect on net flux of water and electrolytes in the rat small and large intestine. They report that in ligated intestinal loops, intravenous calcitonin gene-related peptide (CGRP) induced colonic fluid secretion but had no effect on the small intestine. Also they report using a single-pass perfusion technique, that they observed an immediate dose-dependent secretion of water by the rat colon upon intravenous administration of CGRP and also that the net secretion of sodium, potassium, and chloride were also raised. They suggest the implications of these observations for the possible involvement of high circulation concentrations of CGRP in the watery diarrhea syndrome accompanying medullary thyroid carcinoma.
Further, it was reported by Keates et al., Gastroenterology 114:956-64(1998), “CGRP Upregulation in dorsal root ganglia and ilea mucosa during Clostridium difficile toxin A-induced enteritis in mice” that CGRP may play a role in toxin-A mediated diarrhea and that a CGRP antagonist substantially inhibited toxin-A mediated diarrhea and inflammation.
In addition, Picard et al. reported in International Journal of Radiation Biology, (2001), Vol. 77, No. 3, pp. 349-356, “Presence of protective role of afferent nerves in early intestinal mucosal alterations induced by abdominal irradiation in rats” that CGRP levels increase after abdominal irradiation and particularly in radiation enteritis a condition characterized by diarrhea and other inflammatory reactions.